The human DF3/MUC1 transmembrane glycoprotein is aberrantly overexpressed by breast and other types of carcinomas (Kufe et al., 1984). MUC1 expression is localized to the apical borders of normal secretory epithelial cells. In carcinoma cells, loss of polarity is associated with expression of MUC1 at high levels over the entire cell surface (Kufe et al., 1984). Significantly, overexpression of MUC1 blocks apoptosis and is sufficient to confer cellular transformation (Li et al., 2003b). The fall-length MUC1 protein (MUC1-REP) is cleaved into N- and C-terminal subunits (N-ter (or ectodomain, “ED”) and C-ter) that reside as a heterodimer at the cell membrane (Ligtenberg et al., 1992; Parry et al., 2001). The >250 kDa N-terminal ectodomain contains variable numbers of conserved 20 amino acid tandem repeats (VNTR region) that are extensively modified by O-glycosylation (Gendler et al., 1988; Siddiqui et al., 1988). The ˜25 kDa C-ter includes an extracellular region of 58 amino acids (or extracellular domain, “ECD”), a 28 amino acid transmembrane domain and a 72 amino acid cytoplasmic tail. β-catenin, a component of the adherens junction of mammalian epithelial cells, binds directly to a SAGNGGSSL motif in the MUC1 cytoplasmic domain (Yamamoto et al., 1997). The SAGNGGSSL motif also functions as a binding site for γ-catenin (plakoglobin) (Yamamoto et al., 1997). The MUC1 C-ter is expressed at the cell membrane and in the nucleus where it colocalizes with β-catenin (Li et al., 2003b; Li et al, 2003c) and γ-catenin (Li et al., 2003b).
The available evidence indicates that MUC1 functions in integrating signals from the Wnt and ErbB pathways. Glycogen synthase kinase 3β (GSK3β), an effector of Wnt signaling, phosphorylates MUC1 on serine in a SPY site adjacent to that for β/γ-catenin binding (Li et al., 1998). GSK3β-mediated phosphorylation of MUC1 decreases the interaction between MUC1 and β-catenin (Li et al., 1998). The tyrosine in the SPY site is phosphorylated by c-Src and, in contrast to the effects of GSK3β, c-Src increases the interaction between MUC1 and β-catenin (Li et al., 2001a). Phosphorylation of the MUC1 tail by protein kinase Cδ (PKCδ) also contributes to the interactions between MUC1 and β-catenin Ren et al., 2002). Other studies have shown that MUC1 forms a complex with the epidermal growth factor receptor (EGFR) (Li et al., 2001b; Schroeder et al., 2001). Stimulation of cells with EGF is associated with tyrosine phosphorylation of the SPY site and increased formation of MUC1-β-catenin complexes (Li et al., 2001b). Conversely, exposure of cells to heregulin (HRG), a ligand for ErbB receptors, induces binding of MUC1 and γ-catenin (Li et al., 2003c).
A number of splice variants of MUC1 have been described, including transmembrane proteins that lack the entire VNTR region. Such isoforms include MUC1/Y, MUC1/X and MUC1/Z (Zrihan-Licht et al., 1994; Baruch et al., 1997; Oosterkamp et al., 1997; Obermair et al., 2002).